This invention relates to treatment of hyperkinetic movement disorders such as, for example, tardive dyskinesia and the hyperkinesia associated with Huntington's Disease. Tardive dyskinesia ("TD") is an extrapyramidal hyperkinetic movement disorder that appears in some patients being treated by administration of certain antipsychotic agents ("neuroleptics"). A progressive dyskinesia ("chorea") is characteristic of Huntington's Disease ("HD").
Hyperkinetic movement disorders are characterized by non-purposeful, repetitive, disordered motor acts, variously termed "compulsive", "convulsive", "rhythmical", or "stereotyped". The term "stereotypy" refers here to a repeated behavior that appears repetitively with slight variation or, less commonly, as a complex series of movements. In humans stereotypies can be psychogenic (e.g., tics), idiopathic (as in, e.g., Tourette's syndrome and Parkinson's Disease, genetic (as in, e.g., the chorea characteristic of Huntington's Disease), infectious (as in, e.g., Sydenham's Chorea), or, as in TD, drug-induced.
The most generally accepted theory of the etiology of TD is that chronic administration of the neuroleptic (typically, for example, a butyrophenone such as haloperidol, or a phenothiazine such as fluphenazine) results in a postsynaptic dopamine receptor supersensitivity. Evidence for such supersensitivity comes from receptor binding studies showing specific changes in striatal dopamine receptors (see, e.g., Burt et al. (1977), Science, Vol. 196, pp. 326-28; Muller et al. (1978), Psychopharmacology, Vol. 60, pp. 1-11; and, more recently, McGonigle et al. (1989), Synapse, Vol. 3, pp. 74-82; and Wilmot et al. (1989), Brain Res., Vol. 487, pp. 288-298); and behavioral studies which have focused on the production of oral stereotypic behaviors resulting from chronic dopamine antagonist treatment alone (Weiss et al. (1977), Psychopharmacology, Vol. 53, pp. 289-93; Waddington et al. (1983), Science, Vol. 220, pp. 530-32). The oral stereotypy produced by chronic neuroleptic treatment in animals has been described as almost identical in physical character to that seen in humans (Ellison et al. (1989), Psychopharmacology, Vol. 98, pp. 564-66). Because spontaneous oral dyskinesias are uncommon in animals receiving neuroleptics (Kawans et al. (1972), Jour. Neural Trans., Vol. 33, pp. 235-46), the administration of a dopamine agonist following two to three weeks of neuroleptic treatment results in an oral stereotypy (Tarsy et al. (1974), Neuropharmacology, Vol. 13, pp. 927-40; Ellison et al. (1988), Psychopharmacology, Vol. 96, pp. 253-57) that has become a widely used animal model of TD (Hall et al. (1982), British Jour. Pharmacol., Vol. 76, p. 233P).
At present opiate antagonists are in use principally in urban emergency care settings, where they are administered to reverse effects of an overdose of heroin or morphine. Naloxone (marketed for example as Narcan.RTM.), the opiate antagonist most often used for this purpose, has a short duration of action, and must be administered parenterally. Naltrexone (marketed for example as Trexan.RTM.), an opiate antagonist that is longer acting than naloxone and can be orally administered, was introduced more recently. Naltrexone is in use principally to treat overdose of an opiate drug, and to treat persons who are physically dependent on opiate drugs, such as, e.g., heroin. Daily administration of naltrexone completely blocks the euphoric effects of opiate agonists such as morphine or heroin, and if administered to persons who are physically dependent on opiate drugs naltrexone precipitates withdrawal.